A Quantitative Approach for Detecting Anxiolytic Drug Effects in the Mouse

描述（由申请人提供）：携带神经基因突变的小鼠细胞系的增殖为研究复杂行为（如焦虑调节）的神经基础提供了新的机会。我们为此目的优化利用小鼠遗传资源的能力严重依赖于行为分析的可靠性和敏感性。尽管用于评估小鼠焦虑相关行为的标准方法已经有了实质性的好处，但人们普遍认为，这种分析在准确性、灵敏度和可重复性方面存在局限性，因此需要开发新的补充方法。我们建议采用一种独特的定量方法来分析老鼠的家笼行为，以解决这个问题。我们将测试调节焦虑的环境和药物操作将影响小鼠在其家庭笼子中表现出的自发行为的协调表达的假设。我们建议对高分辨率的家庭笼子行为数据集进行定量分析，可以为新的焦虑相关行为措施提供高度敏感的评估。该提案包括3个目标。在Aim 1中，我们将研究家庭笼子行为模式对压力源的敏感性，目的是确定潜在的候选焦虑措施。将使用两种被认为在焦虑相关行为的表达上不同的近交系小鼠。在目标2中，将采用药理学验证方法来评估这些措施被已知的抗焦虑和致焦虑药物适当修改的程度。这些措施的特异性将通过检查它们对不知道调节焦虑的行为活性药物的敏感性来探索。在Aim 3中，我们将确定定量的家庭笼行为监测方法在多大程度上可以用于检测慢性5 -羟色胺再摄取阻滞剂氟西汀和三环抗抑郁药地西帕明治疗所产生的慢效抗焦虑作用。已知对慢性氟西汀治疗有不同反应的小鼠品系C57BL/6J和BALB/cJ将用于这些研究。用于确定小鼠焦虑水平的行为评估方法的局限性阻碍了新型焦虑症治疗药物的开发。在这里，我们建议采用我们开发的一种新的定量行为监测方法来推导和验证焦虑状态的新标记。

DESCRIPTION (provided by applicant): The proliferation of mouse lines bearing mutations of neural genes presents new opportunities for inroads into the neural bases of complex behaviors, such as the regulation of anxiety. Our ability to optimally utilize mouse genetic resources for this purpose is critically dependent on the reliability and sensitivity of behavioral assays. Although standard approaches for assessing anxiety-related behavior in mice have been of substantial benefit, widely recognized limitations in the accuracy, sensitivity and reproducibility of such assays warrant initiatives for the development of novel complementary approaches. We propose to adapt a unique quantitative approach to the analysis of mouse home cage behavior to this problem. We will test the hypothesis that environmental and pharmacological manipulations that modulate anxiety will impact the coordinated expression of spontaneous behaviors exhibited by mice in their home cages. We propose that quantitative analysis of high-resolution home cage behavioral datasets can be adapted to provide a highly sensitive assessment of novel anxiety- related behavioral measures. The proposal consists of 3 Aims. In Aim 1 we will examine the sensitivity of home cage behavioral patterns to stressors, with the goal of identifying potential candidate anxiety measures. Two inbred mouse strains believed to differ in their expression of anxiety-related behaviors will be used. In Aim 2, a pharmacological validation approach will be taken to assess the extent to which these measures are appropriately modified by known anxiolytic and anxiogenic drugs. The specificity of these measures will be explored by examining their sensitivity to behaviorally active drugs not known to modulate anxiety. In Aim 3, we will determine the extent to which quantitative home cage behavioral monitoring approaches may be used to detect slow-onset anxiolytic effects produced by chronic treatment with the serotonin reuptake blocker fluoxetine and the tricyclic antidepressant desipramine. Strains of mice known to respond differently to chronic fluoxetine treatment, C57BL/6J and BALB/cJ, will be used for these studies. Limitations in behavioral assessment methods for determining anxiety levels in the mouse are hindering the development of novel therapeutic agents for anxiety disorders. Here we propose to adapt a novel quantitative behavioral monitoring method we have developed to derive and validate new markers of anxiety state.